SUMMARY The current generation of broadly neutralizing HIV-specific monoclonal antibodies (bNAbs) have many exciting applications in HIV-1 prevention, therapy, and cure. Therapeutic administration of bNAbs in HIV- infected individuals is being pursued with the overlapping goals of maintaining plasma virus suppression, enabling Fc-mediated clearance of virus-infected cells, and enhancing host immune responses. Preclinical studies of single and combination bNAbs in simian-human immunodeficiency virus (SHIV)-infected macaques have demonstrated remarkably potent and durable virus suppression, augmentation of anti-HIV immune responses, and possible reductions of the cellular reservoir. In contrast, recent human clinical trials have shown markedly less potency and durability, no effect on the cellular reservoir, and frequent pre-existent and emergent bNAb-resistant variants. The discordant results of pre-clinical SHIV/macaque experiments and human clinical trials highlight several fundamental questions underlying bNAb immunotherapy and the need for a well-characterized SHIV/macaque model of HIV latency in which to study them. Project 1 will capitalize on two recent advances in NHP models to elucidate the determinants of TF SHIV rebound from bNAb immunotherapy: (i) our group's discovery of a novel strategy to create pathogenic SHIVs that retain the antigenic conformation of transmitted/founder (TF) HIV-1 Env and the viral kinetics and persistence properties of primary HIV-1 strains, and (ii) a strategy to place silent genetic tags, or barcodes, within a virus stock, which allows for discrimination of each viral lineage and enables sophisticated modeling of viral kinetics, reactivation and rebound. A central premise of this project is that a well-characterized barcoded-TF SHIV model of latency and virus reactivation will enable delineation of the determinants of viral rebound and elucidate the capabilities, mechanisms, and immunomodulatory effects of bNAb administration. Utilizing this novel TF SHIV model, we will test combination bNAb immunotherapy in the context of treatment interruption after early and late ART initiation and in viremia. Specific Aims of Project 1 are to: 1) determine how bnAb immunotherapy alters virus reactivation, tissues of origin and subsequent virus growth; 2) identify the etiology and impact of neutralization resistance; 3) determine whether treatment interruption or bNAb immunotherapy change the size of the latent reservoir; and 4) determine how bNAbs modulate host antibody and T cell responses. Results from these studies will elucidate the viral kinetics and immunologic characteristics of latency and viral rebound in a novel, biologically relevant TF SHIV model that could facilitate broad testing of therapeutic and eradicative strategies. Further, the determination of bNAb immunotherapy's clinical efficacy, mechanisms of bNAb mediated virus suppression, effects on the archived viral reservoir, and impact on host immune responses will inform the design of future bNAb immunotherapeutic strategies for virus suppression and eradication.